- Innate immunity refers to host defense strategies first employed by primitive multicellular organisms prior to the evolution of antigen receptors on B and T cells (acquired immunity) in vertebrates. One role of the innate immune system is to translate "injury"--whether traumatic, radiant, or infectious--into a biochemical signal that can recruit cells that mediate host defense. Recently, it has become clear that plants, insects, and vertebrates all share a common post receptor signaling pathway that leads to activation of the NFkB family of transcription factors, resulting in the induction of a set of genes that protect the host from microbial infection. The intracellular domain of the IL-1 R type 1 (IL-1 R1 ) is homologous to that of the Drosophila melanogaster Toll protein. Activation of the IL-1R induces NFkB-mediated transcription to many genes, including cytokines, chemokines, and adhesion molecules. Activation of Toll through its ligand, Spaetzle, induces NFkB-generated antifungal and antibacterial peptides, and the human Toll homolog was recently shown to signal through the interleukin-1 receptor-associated kinase (IRAK), indicating that human Toll and IL-1 share a common signaling pathway. While the human Toll ligand remains unknown, regulation of ligand receptor interactions involving IL-1 have been extensively studied. Recent evidence suggests that the acquired immune system can be influenced by, and is dependent on, the innate immune system. The present proposal is a competitive renewal of a grant first funded in 1989, and is based on the hypothesis that IL-1 in skin is at the nexus of innate and acquired immunity and is central to cutaneous immunosurveillance against both microbial infection and skin cancer. While the innate immune system is responsible for a first response to injury (traumatic, radiant, infectious), the adaptive immune system (B and T lymphocytes) is responsible for specific pathogen recognition and disposal. There is much evidence that the acquired and innate arms of the immune system are highly interdependent. The principal investigator proposes that release of stored and/or induced IL-1 alpha or beta by skin leads to production of chemokines and induction of endothelial adhesion molecules in dermis that specifically recruit CLA+, or skin homing T cells in an antigen-independent fashion. Because CLA+ memory T cells are greatly enriched for T cells specific for antigens originally encountered in skin draining lymph nodes (e.g., antigens that entered the host via skin), injury, infection, or trauma to skin rapidly recruits a selected population of T cells that are likely to recognize environmental antigens and pathogens to which skin is exposed. Other features of IL-1-induced inflammation, including recruitment of dendritic cells and induction of their maturation into potent APC's synergizes with this effect, leading to rapid recruitment of a potent acquired immune system response at the environmental interface. Recognition of antigen in skin by recruited T cells leads to T cell cytokine production, and, ultimately, elimination of the pathogen.